Full DPYD sequencing catches 26% more clinically relevant variants than targeted genotyping
Over a 9-year period, DPYD sequencing identified reportable variants in 12.8% of 7,003 patients tested, compared to 9.3-9.4% that would have been detected by AMP Tier 1/2 targeted genotyping alone. Among the 281 non-Tier variants found by sequencing, over 80% lacked CPIC classification and over 48% were absent from ClinVar. The findings support a transition from targeted genotyping to sequencing for fluoropyrimidine toxicity risk assessment, though a standardised pharmacogenomic variant classification framework is needed.
The original study
DPYD Sequencing Identifies More Clinically Relevant Variants as Compared to Targeted Genotyping.
- Authors
- Moyer AM, Lundquist E, Thoreson EK, Kluge ML, Kotzer KE, Love EM, et al.
- Journal
- Clinical chemistry
- PMID
- 41802113
Original abstract
BACKGROUND: DPYD testing can identify patients at risk for severe toxicity when a standard fluoropyrimidine antineoplastic dose is prescribed. Sequencing-based methods detect rare variants, which require classification. METHODS: DPYD sequencing results over a 9-year period through to 2024 were analyzed. The dataset was filtered to calculate the positive test rate for different genotyping strategies, including targeted analysis of the Association for Molecular Pathology (AMP) Tier 1 and 2 recommended alleles, and as compared to sequencing. Variant classifications based on the laboratory's clinical protocol were compared to ClinVar classifications and designations by the Clinical Pharmacogenetics Implementation Consortium (CPIC) expert panel. RESULTS: A DPYD variant was reported in 12.79% (896/7003) of those tested, with 2.53% (170/7003) of all reports including a variant of uncertain significance. Had only AMP Tier 1 or both Tier 1 and 2 been tested, 9.30% and 9.44% of patients would have received a positive report, respectively. Among the 281 unique, non-Tier 1/Tier 2 variants encountered during sequencing, >80% were not classified by the CPIC expert panel, while >48% were not reported in ClinVar. Variant classifications by our laboratory and those in ClinVar were generally concordant with the CPIC expert panel, despite the lack of a standardized classification system. CONCLUSIONS: While AMP Tier 1 genotyping would have identified most patients at risk for fluoropyrimidine toxicity, sequencing is more comprehensive, identifying 26% more reportable variants compared to targeted genotyping. A standard framework for pharmacogenomic variant classification could facilitate consistent variant classification and a transition from targeted genotyping to sequencing.